rs5936

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000312.4(PROC):c.423G>T(p.Ser141Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 1,549,898 control chromosomes in the GnomAD database, including 362,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.69 ( 36480 hom., cov: 36)

Exomes 𝑓: 0.68 ( 325588 hom. )

Consequence

PROC
NM_000312.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.81

Publications

38 publications found

Variant links:

Genes affected

PROC (HGNC:9451): (protein C, inactivator of coagulation factors Va and VIIIa) This gene encodes a vitamin K-dependent plasma glycoprotein. The encoded protein is cleaved to its activated form by the thrombin-thrombomodulin complex. This activated form contains a serine protease domain and functions in degradation of the activated forms of coagulation factors V and VIII. Mutations in this gene have been associated with thrombophilia due to protein C deficiency, neonatal purpura fulminans, and recurrent venous thrombosis.[provided by RefSeq, Dec 2009]

PROC links:

MIR4783 (HGNC:41874): (microRNA 4783) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR4783 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.017).

BP6

Variant 2-127423296-G-T is Benign according to our data. Variant chr2-127423296-G-T is described in ClinVar as Benign. ClinVar VariationId is 255809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.81 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4 link	c.423G>T	p.Ser141Ser	synonymous_variant	Exon 6 of 9	ENST00000234071.8	NP_000303.1	P04070-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8 link	c.423G>T	p.Ser141Ser	synonymous_variant	Exon 6 of 9	1	NM_000312.4	ENSP00000234071.4		P04070-1

Frequencies

GnomAD3 genomes

AF:

0.692

AC:

105153

AN:

152022

Hom.:

36471

Cov.:

show subpopulations

Gnomad AFR

AF:

0.719

Gnomad AMI

AF:

0.797

Gnomad AMR

AF:

0.754

Gnomad ASJ

AF:

0.692

Gnomad EAS

AF:

0.572

Gnomad SAS

AF:

0.521

Gnomad FIN

AF:

0.685

Gnomad MID

AF:

0.682

Gnomad NFE

AF:

0.682

Gnomad OTH

AF:

0.693

GnomAD2 exomes

AF:

0.678

AC:

100470

AN:

148168

AF XY:

0.661

show subpopulations

Gnomad AFR exome

AF:

0.721

Gnomad AMR exome

AF:

0.833

Gnomad ASJ exome

AF:

0.711

Gnomad EAS exome

AF:

0.562

Gnomad FIN exome

AF:

0.677

Gnomad NFE exome

AF:

0.686

Gnomad OTH exome

AF:

0.686

GnomAD4 exome

AF:

0.680

AC:

951060

AN:

1397762

Hom.:

325588

Cov.:

AF XY:

0.675

AC XY:

465408

AN XY:

689444

show subpopulations

African (AFR)

AF:

0.711

AC:

22409

AN:

31532

American (AMR)

AF:

0.820

AC:

29353

AN:

35790

Ashkenazi Jewish (ASJ)

AF:

0.709

AC:

17841

AN:

25146

East Asian (EAS)

AF:

0.642

AC:

22955

AN:

35768

South Asian (SAS)

AF:

0.522

AC:

41381

AN:

79228

European-Finnish (FIN)

AF:

0.685

AC:

32803

AN:

47888

Middle Eastern (MID)

AF:

0.656

AC:

3570

AN:

5444

European-Non Finnish (NFE)

AF:

0.687

AC:

741677

AN:

1079010

Other (OTH)

AF:

0.674

AC:

39071

AN:

57956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

20267

40535

60802

81070

101337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19178

38356

57534

76712

95890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.691

AC:

105200

AN:

152136

Hom.:

36480

Cov.:

AF XY:

0.688

AC XY:

51165

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.719

AC:

29847

AN:

41534

American (AMR)

AF:

0.754

AC:

11548

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.692

AC:

2399

AN:

3466

East Asian (EAS)

AF:

0.572

AC:

2948

AN:

5150

South Asian (SAS)

AF:

0.520

AC:

2504

AN:

4820

European-Finnish (FIN)

AF:

0.685

AC:

7256

AN:

10588

Middle Eastern (MID)

AF:

0.685

AC:

200

AN:

292

European-Non Finnish (NFE)

AF:

0.682

AC:

46321

AN:

67954

Other (OTH)

AF:

0.686

AC:

1450

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1762

3524

5286

7048

8810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

812

1624

2436

3248

4060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.697

Hom.:

19403

Bravo

AF:

0.704

Asia WGS

AF:

0.548

AC:

1905

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Thrombophilia due to protein C deficiency, autosomal dominant

Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Thrombophilia due to protein C deficiency, autosomal recessive

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

3.3

(source)

DANN

Benign

0.77

PhyloP100

-1.8

PromoterAI

0.0093

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over